The long-term objective of our studies is to define the biological role of the hypothalamic-pituitary-adrenal (HPA) axis and signaling through the glucocorticoid receptor (GR) in both the normal stress response and in psychiatric disease. Dysfunction HPA axis, the endocrine stress response, is specifically associated with vulnerability to major depression, bipolar disorder, anxiety disorders, and schizophrenia. The amygdala is a key nodal forebrain structure for integrating neuroendocrine and behavioral responses to stress, and amygdalar hyperactivity occurs in human depression and HPA hypersecretory states. Moreover, glucocorticoid action in the central nucleus of the amygdala (CeA) has been implicated in mediating a positive feedback loop that potentiates activity of the HPA axis, anxiety, and acquisition or expression of emotionally salient memory. The mechanisms by which these processes occur remain poorly understood, in part because of inadequately specific means for genetic manipulation of CeA function. We will test the hypotheses that glucocorticoid receptors in the CeA regulate behavioral and adrenal responses to stress by control of corticotropin-releasing hormone (CRH) gene expression at this site. Our specific aims will seek to establish a novel CeA-specific GR knockout system, determine the phenotypic consequences of loss of GR function in the CeA for HPA axis regulation and behavior, and determine whether alteration in CRH expression contributes to the resulting behavioral and adrenal axis changes by regional replacement of CRH. Ultimately, our efforts aim to further the understanding of neuroendocrine circuits relevant for psychiatric diseases and promote development of novel therapeutic approaches for these major health disorders. PUBLIC HEALTH RELEVANCE An estimated 40 million people in the United States suffer from a psychiatric disorder, generating an enormous societal and public health burden. The results of our planned studies on the role of glucocorticoid receptor function in the amygdala hold promise for new insights into brain pathways regulating the responses to stress and the genesis and treatment of mental illness.